Angiopep-2-functionalized Cu–Mn oxide nanoplatform for blood–brain barrier penetration and radiotherapy-enhanced cuproptosis in glioma therapy

Glioblastoma (GBM) suffers from a poor prognosis due to its highly invasive nature, limited drug delivery across the blood-brain barrier (BBB), and intrinsic radioresistance. Although radiotherapy (RT) can perturb copper homeostasis and induce cuproptosis, the extent of copper accumulation is typically insufficient for effective tumor suppression. Herein, we develop a multifunctional composite nanoplatform, Mn₃O₄@PDA/Cu₂O-Angiopep-2 (MPCA), that integrates BBB penetration, radiosensitization, and copper-mediated cytotoxicity. Angiopep-2 facilitates LRP1-mediated BBB transcytosis and glioma targeting, X-ray diffraction and X-ray photoelectron spectroscopy confirmed the coexistence of crystalline Mn₃O₄ and Cu₂O phases and the predominantly Cu(I) state of copper in the composite nanoplatform. Following cellular internalization, MPCA functions as both a copper reservoir and a reactive oxygen species (ROS) amplifier. The Cu₂O component enables sustained copper release, whereas Mn₃O₄ enhances irradiation-induced oxidative stress. Under mildly acidic conditions, MPCA exhibits increased copper release, while X-ray irradiation amplifies ROS generation, with the strongest oxidative response observed under combined acidic and irradiation conditions. Mechanistically, MPCA combined with RT increases intracellular copper accumulation, disrupts copper homeostasis, and exacerbates mitochondrial oxidative stress, thereby inducing cuproptosis-associated mitochondrial dysfunction. These effects markedly enhance the radiosensitivity of GBM and inhibit orthotopic tumor growth. Overall, this study presents an Angiopep-2-functionalized Cu-Mn oxide composite nanoplatform that combines BBB targeting with copper-mediated radiosensitization, providing a promising strategy for GBM radiotherapy.